Although numerous factors contribute to obesity, recent studies have established a critical role for central melanocortin pathways in the control of feeding behavior and energy balance. Genetic deficiency of melanocortin receptor 4 (MC4-R) or POMC produces obesity in both mice and humans. Central administration of melanocortin peptides reduces feeding and obesity. These observations provide a compelling basis for the development of melanocortin agonists as drug treatments for obesity and diabetes. Furthermore, the melanocortin pathway is therapeutically unexplored. The overall goal of this application is to develop orally active and selective agonists of MC4-R. Previously we used human MC4-R receptor binding and signal transduction assays in high throughput screens to identify a set of small molecule MC4-R agonists with low micromolar potencies. In Phase I we will use high throughput parallel synthesis to optimize several compound families and develop lead molecules with high potency. We will evaluate the activity of these agonists against the full panel of MC receptors to construct a selectivity profile. With multiple compounds identified in the primary screens, we expect improvements generated by high throughput parallel synthesis will provide compounds with the necessary pharmacological properties to achieve lead development candidates in Phase II. PROPOSED COMMERCIAL APPLICATIONS: This research, if successful, will result in small molecule agonists of the melanocortin receptor 4 that selectively inhibit the feeding response. Orally active forms of a small molecule MC4-R agonist would provide a novel therapeutic strategy for indications such as obesity and diabetes.